1. Field of the Invention
Applicant""s invention relates to magnetic resonance technology as applied to the non-invasive in-situ measurement of bone porosity, pore size distribution, and other bone properties including aging.
2. Background Information
Bone is a porous material in nature. In human bone, there are three major natural cavities or xe2x80x9cvoidsxe2x80x9d. Among them, Haversian and Volkmann""s canals play a role in accommodating longitudinal and transverse vascular vessels to transport cells, nutrients, and proteins needed for metabolism inside the bone. Besides, they provide surfaces for bone resorption and formation of cells (osteoclasts and osteoplasts, respectively) to attach to during bone remodeling processes. The diameter of the canals is on the order of 50 microns, with a length of a few millimeters. Cohen, J. and Harris, W. H., xe2x80x9cThe Three Dimensional Anatomy of the Haversian System,xe2x80x9d Journal of Bone and Joint surgery, 40-A: 419, 1958. In addition, bone has many small ellipsoidal cavities called lacunae that contain bone cells called osteocytes. Although the role of osteocytes is still not well understood, it has been known that these cells may greatly contribute to the initiation of the bone remodeling process by sensing changes in stress or strain fields around them. These quasi-spherical voids have a diameter of approximately 5 microns. Johnson, J. C., xe2x80x9cThe Kinetics of Skeletal Remodeling,xe2x80x9d Birth Defects Original Article Series, 2: 66, 1966. Furthermore, these osteocytes are interconnected by small capillary channels (termed xe2x80x9ccanaliculixe2x80x9d) emanating from the vascular vessels. These canaliculi are about 0.5 micron in diameter, and are considered to be responsible for delivering nutrients and relaying signals between the cells. Johnson, J. C., xe2x80x9cThe Kinetics of Skeletal Remodeling,xe2x80x9d Birth Defects Original Article Series, 2: 66, 1966. It is noteworthy that the vascular canals are one order greater in diameter than lacunae, and lacunae are one order greater in diameter than canaliculi.
Previous studies have shown the overall porosity of bone has a significant effect on the mechanical strength of bone. In a comprehensive review on porosity of bone, Martin described that small changes in porosity would lead to significant changes in the stiffness and strength of bone for both compact and spongy bone. Martin, R. B., xe2x80x9cPorosity and Specific Surface of Bone,xe2x80x9d CRC Critical Reviews in Biomedical Engineering, 10 (3):179, 1984. In a recent study, McCalden reported that the effect of age-related increase of bone porosity on bone properties is manifested in the decreased capacity of bone to absorb post-yield plastic energy. McCalden, R. W., McGeough, J. A., Barker, M. B., Court-Brown, C. M., xe2x80x9cAge-related Changes in the Tensile Properties of Cortical Bone: The Relative Importance of Changes in Porosity, Mineralization, and Microstructure,xe2x80x9d Journal of Bone and Joint Surgery (Am.), 75(8):1193, 1993. Since changes in numbers and sizes of these natural cavities are directly related to the remodeling processes and biomechanical properties of bone, a direct sensing technique to detect such changes in bone has been long wanted. However, particularly for compact bone, none of the current techniques can quantitatively assess the porosity and pore size distribution in a non-invasive manner.
Microgravity induced bone loss has been a major concern for the health of astronauts. Under weightless conditions, the mechanical stimuli to the skeleton is significantly reduced. Based upon the widely accepted theory of bone adaptation to a mechanical environment, such disuse may trigger the bone remodeling processes leading to the reduction of bone mass. However, the underlying mechanisms for such changes still remain unclear. In the past, biochemical assays were widely used to monitor the bone remodeling process in animal models and to study the mechanisms of such bone mass loss. Since all these assays can be performed in an indirect manner, only qualitative results can be obtained. Thus, it would provide great opportunities for researchers to investigate the mechanisms of bone mass loss if a non-invasive and direct monitoring of the bone remodeling process is available. In a sense, by monitoring changes in these natural voids, i.e. Haversian canals, lacunae, and canaliculi, in situ, one may assess the process of bone remodeling.
Magnetic resonance (MR) imaging (MRI) techniques have been used to study soft tissue and the gross skeletal structure. Recently high resolution MR imaging has been used to resolve the larger porosity cavities in trabecular bone structure in vitro at high magnetic field strengths, and in vivo using clinical scanners at fields of 1.5 T. Chung, H., Wehrli, F. W., Williams, J. L., Kugelmass, S. D., xe2x80x9cRelationship between NMR Transverse Relaxation, Trabecular Bone Architecture and Strength,xe2x80x9d Proc. Nat""l. Acad. Sci, USA 90:10250, 1993; Hipp, J. A., Jansujwicz, A., Simmons, C. A., Snyder, B., xe2x80x9cTrabecular Bone Morphology Using Micromagnetic Resonance Imaging,xe2x80x9d J. Bone Mineral Res. 11:286, 1996, Majumdar, S., Gies, A., jergas, M., Grampp, S., Genant, H., xe2x80x9cQuantitative Measurement of trabecular Bone Structure Using High Resolution Gradient Echo Imaging of the Distal Radius,xe2x80x9d Proceeding of the Society of Magnetic Resonance in Medicine, New York, P455, 1993; Jara, H., Wehrli, F. W., Chung, H., Ford, J. C., xe2x80x9cHigh-resolution Variable Flip Angle 3D MR Imaging of Trabecular Microstructure in Vivo,xe2x80x9d Magnet Reson Med 29:528, 1993. However, this MR imaging technique is not suitable for resolving the smaller pores and voids in compact bone. Compact bone does not generate any detectable MR images of the porosity structure. On the other hand, nuclear magnetic resonance (NMR) spin-spin (T2) or spin-lattice relaxation time (T1) measurements and analyses have been used to determine the porosity and pore size distribution in different porous media. Gallegos, D. P., Munn, K., Smith, D. M., and Stermer, D. L., J. Colloid Interface Sci. 119:127, 1987; Glaves, C. L., and Smith, D. M., J. Membr. Sci. 46:167, 1989; Howard, J. J., and Kenyon, W. E., Mar. pet. Geol. 9:139, 1992; Kenyon, W. E., xe2x80x9cPetrophysical Principles of Applications of NMR Logging,xe2x80x9d The Log Analyst, Mar.-Apr. p21, 1997. For instance, the low field NMR well logging technique uses a similar principle to detect the porosity, pore size distribution and permeability in oil reservoirs where the fluids (oil and water) are in pores in the rock structure-ranging from submicron to submillimeter. This MR technique is based upon the fact that proton relaxation time of fluid (water, oil, etc.) in porous media is shorter than that of pure fluid itself and is a function of the pore size. The enhanced relaxation rate (1/T1 or 1/T2) of fluid in a heterogenous system is accounted for by the presence of a relaxation xe2x80x9csinkxe2x80x9d at the surface of the pores. Owing to the interactions between the fluid molecules and the solid surface of the pore walls, protons near these surfaces relax faster than in the bulk. The fluid in large pores tends to relax slower (longer relaxation time T1 or T2) than fluid in small pores because of the different relative amounts of surface area compared to the volume of bulk fluid. Thus, the measured relaxation profile provides information about pore size distribution, or more precisely, the pore volume to pore surface area ratio distribution while the total amplitude of the pore fluid signal provides a measure of the porosity.
It has been known that water makes up a major portion of the fluid in the bone natural cavities or pores which is similar to water saturated in a rock. Therefore, the amplitude of the T2 relaxation time data can be used to determine the porosity of the bone, and its inversion T2 relaxation distribution can be transformed to the pore size distribution if the surface relaxivity constant is known. NMR T2relaxation rate (1/T2)is known to depend on a surface-to-volume ratio with the proportionality of the surface relaxivity constant. Since bone has chemical, molecular, and cellular components inside and is more complex than water saturated rock, we may define the bone relaxation time distribution as corresponding to the effective pore size distribution. On the other hand, the chemical, molecular and cellular components are at least similar in all types of bone, therefore, the differences in properties of bone must be in some way related to differences in microstructures which organize or control these elements. Martin, R. B., and David, B. B., xe2x80x9cStructure, Function, and Adaptation of Compact Bone,xe2x80x9d Raven Press, New York, 1989. Thus the effective pore size distribution can provide important microstructure information in bone and be used to study the remodeling processes and biomechanical properties of bone. Meanwhile, from now on, we are going to omit the xe2x80x9ceffectivexe2x80x9d in effective pore size for convenience.
It is an object of the present invention to provide a novel means to use nuclear magnetic resonance to characterize human bone including compact bone.
Still another object of the present invention is to provide a novel means to use nuclear magnetic resonance to characterize the porosity and porosity changes in human bone including compact bone.
Yet another object of the present invention is to provide a novel means to use nuclear magnetic resonance to characterize the pore size distributions and the changes thereof in human bone including compact bone.
It is another object of the present invention to provide a novel means to use nuclear magnetic resonance to characterize age-related human bone including compact bone.
Still another object of the present invention is to provide a novel means to use nuclear magnetic resonance to measure porosity and pore size distributions in human bone in situ.
Another object of the present invention is to provide a novel means to use nuclear magnetic resonance to measure porosity and pore size distributions in human bone, and changes thereof, in situ.
Yet another object of the present invention is to provide a novel means to use nuclear magnetic resonance to non-invasively monitor the condition or deterioration of human bone, including compact bone, as a person ages, and changes in the bone as a person exercises, intakes different food and medicinal formulations, and as a person gains or losses weight, becomes more or less mobile, or is exposed to different gravitational fields.
It is yet another object of the present invention to provide a novel means to use nuclear magnetic resonance that utilizes T2 relaxation data and relaxation spectra, including inversion relaxation spectra, to determine pore size distribution and porosity in human bones including compact bones.
In satisfaction of these and related objectives, Applicant""s present invention provides for a means to utilize magnetic resonance technology to non-invasively measure bone porosity, pore size distribution, and other bone properties, including aging, in situ. The significance of this invention is to provide a useful technique for diagnosis for space medicine as well as other clinical applications including living subjects.